Cancer (tumor) is the leading cause of death in Japan, and the number of patients has increased every year. Accordingly, development of highly effective and safe agents or therapies is strongly desired. Multiple myeloma, a type of hematopoietic tumor, is an incurable B cell tumor that develops abnormality in the final phase of B cell differentiation. Clinically, the course of multiple myeloma is similar to that of end-stage plasma cell leukemia. It is a neoplasm characterized by accumulation of cloned plasma cells, and it often involves the secretion of an immunoglobulin chain. In bone marrow infiltration caused by the tumor cells, uncontrollable growth of myeloma cells involving various complications such as anemia, hypoglobulinemia, or infection with bacteria is observed. In the case of multiple myeloma, the level of interleukin 6 (IL6) is elevated and then the osteoclast is enlarged, which induces bone pain, bone fracture, and hypocalcemia. High-level myeloma immunoglobulin and hypocalcemia often involve kidney failure.
Up to the present, various therapies have been attempted on multiple myeloma patients, although clinical effects on patients as a whole are still low. Multidrug therapy using melphalan and prednisolone is a standard chemotherapeutic regimen. This therapy is intermittently continued for approximately 2 years, and the symptoms go into remission. However, relapses are still observed and the patient dies (Alexanian et al., New England J Medicine, 1994, Vol. 330: 484). These agents exhibit toxicity to normal cells instead of acting specifically on tumor cells alone. Thus, serious side effects develop, and therapeutic effects are limited. Since the 1980s, ultra high-dose chemotherapy with hematopoietic stem cell transplantation has been still actively investigated, although its clinical effect remains low.
In order to reduce toxicity to normal cells, the use of a targeting antibody conjugated with a radionuclide or other cytotoxic substances has been attempted (Goldenberg, Semin Nucl Med., 1989, Vol. 19: 332). However, the ratio of the targeting antibody to be incorporated into the tumor cell is generally low. It is no more than 0.01% to 0.001% of the total amount injected (Vaughan et al., Brit. J Radiol., 1987, Vol. 60: 567). The development of an antibody that can be rapidly localized (internalized) in the target cell can improve the effectiveness of the therapy and reduce the side effects thereof. This can be realized because such an antibody binds to chemically synthetic toxins or therapeutic reagents such as anticancer agents or radionuclides, thereby rapidly emitting these cytotoxic substances in the cells.
Antibody therapies targeting multiple myeloma have been heretofore attempted. IL-6 has been considered to be a major growth factor for multiple myeloma cells (Kawano et al., Nature, 1988, Vol. 332: 83; Klein et al., Blood, 1991, Vol. 73: 517). Accordingly, therapies have been attempted on multiple myeloma patients using a neutralizing antibody against IL-6 or IL-6 receptor for the purpose of blocking the IL-6 signal transduction system. Although the proliferation of multiple myeloma cells was inhibited in patients who had experienced changes of the disease to leukemia, tumors recurred and clinical effectiveness has not yet attained (Bataille et al., Blood, 1995, Vol. 86: 68; Van Zaanen et al., Br J Haematol., 1998, Vol. 102: 783; the Journal of the Japan Society for Clinical Immunology, 1997, Vol. 20: 87). Further, myeloma cell-expressing antigens such as CD19 (Grossbard et al., Br J Haematol., 1998, Vol. 102: 509), CD20 (Hussein et al., Blood, 1999, Vol. 94 [Suppl.1]: 313), CD38 (Maloney et al., Semin Hematol., 1999, Vol. 36 [Suppl.3]: 30), CD54 (Huang et al., Cancer Res., 1995, Vol. 55: 610), CD138 (Wijdenes et al., Br J Haematol., 1996, Vol. 94: 318), or Muc-1 (Treon et al., Blood, 1999, Vol. 93: 1287) have been reported as candidates for the target antigens for the antibody therapy, although none thereof has yet been put to practical use.
Recently, the bone marrow stromal antigen 2 (“BST2,” which may be referred to as “HM1.24 antigen”) has been reported as an antigen that is expressed at high level in the myeloma cells (Goto et al., Blood, 1994, Vol. 84: 1922; Ohtomo et al., Biochem Biophys Res Commun., 1999, Vol. 258: 583). BST2 is a type II transmembrane glycoprotein having a molecular weight of approximately 30 kDa and comprising 180 amino acid residues. A homodimer is formed by S—S bond and expressed on a cytoplasmic membrane. A BST2 protein is not expressed in, for example, a normal peripheral blood cell, bone marrow cell, reactive lymphocyte, liver, kidney, or heart, although it is highly specifically expressed in the plasma cell and in the myeloma cell. Detailed biological activities are not yet known, although BST2 is considered to be associated with terminal B cell differentiation (Ishikawa et al., Genomics, 1995, Vol. 26: 527). Regarding an antibody against human BST2, a mouse monoclonal antibody, which was prepared by immunizing a nonhuman mammalian animal such as a mouse with a human BST2 expressing cell line, has been reported (Goto et al., Blood, 1994, Vol. 84: 1922). Also reported is a chimeric antibody that comprises a variable region of this mouse monoclonal antibody and a constant region of human immunoglobulin (Ozaki et al., Blood, 1999, Vol. 93: 3922). When this antibody was administered ten days after the injection of the myeloma cells to a human myeloma cells-transplanted SCID mouse, tumor growth was inhibited (Ozaki et al., Blood, 1997, Vol. 90: 3179). The antibody therapy for multiple myeloma that utilizes BST2 as a target antigen is expected to be promising. Since the expression of BST2 is reported in other lymphoid tumors as well as in myeloma, the anti-BST2 antibody therapy could be effective on those tumors. These antibodies, however, do not have activity generating BST2 modulation by their binding (Ozaki et al., Ketsueki, Shuyouka (Blood, Tumors), 2000, Vol. 41: 128), and any anti-BST2 antibody that induces rapid internalization, from which enhanced effectiveness of chemotherapeutants or therapeutic reagents such as radionuclides and reduced side effects can be expected, has not yet been reported at all. In general, it is known that an antibody that binds to an antigen protein expressed on the cell surface and induces internalization into the cells can be obtained. It is not always clear whether or not such an antibody can be obtained regarding all the cell surface antigens.